The objective of this renewal application is to elucidate the functional importance of the Natriuretic Peptide System (NPS) in the integrative control of cardiorenal homeostasis with a specific focus upon the pathophysiology and therapeutics of congestive heart failure (CHF) addressing the following working hypothesis. The NPS consisting of the cardiac hormones ANP and BNP and the endothelial cell-derived peptide CNP is activated by ventricular dysfunction representing a protective neurohumoral response that delays progressive cardiac remodeling via renal, vascular and neurohumoral mechanisms which unload the heart. This beneficial neurohumoral mechanism is progressively compromised by the development of a relative NPS deficiency and NPS resistance. Importantly, natriuretic peptide hormone replacement therapy and co-inhibition of neutral endopeptidase (NEP) and angiotensin-converting enzyme are novel strategies which delay the progression of CHF. Recognizing the increase of dietary sodium intake in the US, the hypothesis that dietary sodium excess contributes to progressive ventricular remodeling via up-regulation of NEP despite the suppression of the renin-angiotensin-aldosterone system (RAAS) will also be investigated. We propose integrative physiological studies in a mouse model in which ANP is genetically absent and in a canine model of progressive left ventricular dysfunction (PLVD) with and without experimentally induced ANP deficiency. Therapeutic strategies will include the chronic administration of native natriuretic peptides, novel designer peptides and a possible fourth new member of the NPS-DNP. We will define the potential negative impact of dietary sodium excess upon cardiac remodeling and CHF and establish the role of up-regulation of NEP in response to high sodium diet. We will also employ the use of biomarkers BNP and Cardiotropin-l (CT-1) to detect CHF and cardiac remodeling, The Specific Aims are: Aim 1: Establish that the genetic absence of AN? in the mouse is characterized by progressive cardiac remodeling and overt CHF which may be prevented by ANP hormone replacement therapy. Aim 2: Establish in a canine model of PLVD that the presence of an ANP deficiency is characterized by the accelerated development of cardiac remodeling and overt CHF which can be prevented by ANP hormone replacement therapy. Aim 3: Establish that novel therapies that go beyond AN? hormone replacement therapy and are based upon the properties of the NPS delay the progression and severity of progressive cardiac remodeling and overt CHF. Aim 4: Establish that dietary sodium excess accelerates the development of cardiac remodeling and overt CHF in part via up-regulation of NEP.